ABSTRACT Osteoarthritis (OA) represents a significant cause of disability worldwide in individuals aged 65 and older, a rapidly growing segment of our population. The knee is the most commonly affected joint with pain being the primary symptom, negatively impacting physical, cognitive, and emotional functioning. Symptomatic knee OA has been traditionally attributed to peripheral mechanisms, but measures of joint damage only modestly account for the presence or severity of OA-related pain. The neuropeptide oxytocin (OT) has been recognized as a mediator of endogenous analgesia in animal and human studies. However, little is known about the neurobiological mechanisms underlying OT's pain-relieving properties. This proposal is based on a mechanistic model of OT's analgesic effects leveraging pilot data supporting efficacy and safety of self-administered intranasal OT over 4-weeks in older individuals. Relative to placebo (P), daily administration of intranasal OT diminished self-reported pain intensity, reduced experimental pain sensitivity, and increased self-reported physical and emotional functioning. Further, participants treated with OT, compared to P, showed decreases in brain metabolite concentrations associated with inflammation. Thus, our overarching goal is to evaluate the effects of intranasal OT on pain and function in aging and to determine the extent to which central and peripheral inflammatory mechanisms contribute to these analgesic responses. We aim to 1) determine the effect of intranasal OT administration on clinical and experimental pain sensitivity in older adults with symptomatic knee OA and 2) characterize inflammatory mechanisms contributing to the inter-individual variability in analgesic responses to OT. Older adults with symptomatic knee OA will self-administer intranasal OT or P over 4 weeks using a double-blinded, parallel study design. With strong support from the University of Florida and the McKnight Brain Institute, our interdisciplinary project, using a comprehensive multi-methods approach, will be the first to determine the potential benefit of OT as a novel analgesic therapy for knee OA pain in aging. OT is currently used in obstetrics and may be an inexpensive, effective method for pain management in older adults with little potential for addiction. Embedded in a biopsychosocial framework, our proposal will help pave the way for future investigations using a mechanism-based treatment optimization strategy for individuals suffering from chronic pain.